Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions

ABSTRACT

A process for the production of a solid dispersion of at least one therapeutic agent in a hydrophilic carrier having enhanced solubility in an aqueous media comprising dissolving at least one therapeutic agent in a volatile organic solvent containing a very hydrophilic polymer and evaporating the solvent to dryness to form a co-precipitate of therapeutic agent and hydrophilic polymer and the resulting products and their therapeutic method of use.

It has been known for several years that by the side of classicexploration of the pharmacological and toxicological properties of thedrugs, one takes care more and more on the quantitative aspect of theresorption of the active component. The kinetics become more and morethe object of systematic studies because the intensity of the responseand sometimes the nature thereof, are a function of the concentrationobtained at the level of the site of action. The significance of thesestudies on pharmacokinetics and bio-availability have shown the interestof the modifications brought during the preparation of the galenicforms, mainly for the ones adapted for administration by the digestivetract.

Drugs with poor solubility in water or hardly salifiable during thepassage in the stomach are only partially resorbed. The prior literaturehas shown that the digestive resorption might be modified in a favorableway by the study of the particle size, by the adjunction of non-ionicsurfactants as well as by the adjunction of a solubilizing agent.

The micronization which suitably increases the external specific surfaceof a powdery product yet constitutes an approach to the problem, is onlyconvenient for some pharmaceutical forms, such as suspensions or softgelatin capsules. It cannot be a general solution to this problem. Theadjunction of surfactants can increase the solubility of activecomponents and thereby, improve the kinetics of resorption, but cannotnecessarily allow obtaining higher blood levels. Moreover, it is oftennecessary to add very important amounts (25 to 50%) of a surfactant toobtain a defined result. This improvement in the passage by thedigestive tract seems to result from a decrease in the superficialtension involving an increase of the digestive mucous permeability.

The beneficial effect obtained by adding an emulsifying agent andespecially a fatty acid ester of a glucid proceeds from a differentprinciple. This ester increases the molecule lipophily and makes passagethrough the intestinal barrier more easy to clear. Nevertheless, thistype of process gives some result only with very lipophilic moleculesand requires high concentrations of such fatty acid esters of glucid.

It is also known that, for active substance absorption, thegastro-intestinal tract level of which is limited due to their lowsolubility in biological liquids, one of the possibilities offered tothe galenist for the improvement of kinetics of dissolution is theproduction of solid dispersions. These solid dispersions (defined byChiou et al in J. Pharm. Sci., Vol. 60, pp. 1281-1302, 1971) constitutesystems which, depending on the process used for their production, maypresent different structures (see Ford, Pharm. Acta. Helv., Vol. 61,3,pp. 69-88, (1986) Bloch et al, Pharm. Acta. Helv., Vol. 62, pp. 23-27,(-1987)), corresponding to different crystallographic states. Thevitreous state, though it is a solid state, draws near to a liquid statefor its structural disorder. It is a little orderly state, easy to breakand which improves substantially the rate of dissolution for lesssoluble components. Nevertheless, despite the great number ofpublications relating to the production of solid dispersions, especiallyfor Macrogols or Poloxamers, this technique has not known any importantdevelopment because of its lack of generality. In some cases, the rateof dissolution is great. In other cases, the rate of dissolution isweaker and makes one's way toward an asymptotic value. For the same drugand for the same concentration, it has been established very significantvariations in rates of solubility in terms of the nature of co-fusingagent and even in certain cases, the impossibility to obtain a completesolubilization of the active component, even after a protracted time ofcontact.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a novel process for drypharmaceutical products and the co-precipitate formed thereby which,when administered orally has a faster and greater resorption.

It is another object of the invention to provide improved pharmaceuticalcompositions and method of use.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel process of the invention for the production of a soliddispersion of at least one therapeutic agent in a hydrophilic carrierhaving enhanced solubility in an aqueous media comprises dissolving atleast one therapeutic agent in a volatile organic solvent containing avery hydrophilic polymer and evaporating the solvent to dryness to forma co-precipitate of therapeutic agent and hydrophilic polymer.

The fact is that the resorption in the digestive tract takes place overa short time and in a reduced space. It is therefore of importance that,in the formulation of the invention, the active component will beconveyed quickly and completely in a solubilized form as the absorptionrate will be dependent therefrom. It appeared that the best absorptionkinetics were obtained with dispersions in very hydrophilic polymers andespecially in polyvinylpyrrolidone in a co-precipitated form. Adissolution rate of 80% within 10 minutes at least has been obtained.Applicants' studies have shown that the dissolution rate will beincreased still more when the organic solvent also contained asurface-active agent which further improves the wetability of the activeingredient and optionally limits the phenomenon of growth of crystalswhich operates during the conservation of solid dispersions and leads toa decrease of the kinetics of dissolution as a function of time.

Since 1961, date when Sekiguchi et al. Chem. Pharm. Bull., Vol. 9(1961), pp. 866-872, have proposed for the first time the use of soliddispersion, about 300 publications describing the mode of production ofthese systems as well as their physico-chemical, galenical, andpharmaceutical properties have issued in the literature. Thispharmaceutical technique widely described in the literature, concernmore than a hundred of active ingredients dispersed in at least thirtyor more various hydrophilic carriers and has been made the subject ofmany synthetic reviews Bloch et al/Chiou et al/Duchene Pharma., Vol. 1,(11), pp. 1064-1073 (1985)/Ford/Puisieux et al Pharma, Prob. et Tech.,Vol. 305, pp. 11-20 (1981).

The solid dispersions are systems in which one or several activeingredients are dispersed in the solid state (microparticular, evenmolecular) in an inert solid vehicle (Chiou et al). These soliddispersions have to be made distinct from mere mixture of powdersdesignated under the name of physical mixture. Two methods are currentlyused for the preparation of solid dispersions: the method ofmelting/solidification which leads to the formation of co-melted—and themethod of dissolution/evaporation which leads to the formation ofco-precipitates. A mixed method resulting from the combination of bothpreceding methods, is sometimes cited but appears to be seldom utilized.

The process of the invention utilizes the formation of co-precipitatesby means of dissolution—evaporation. The very hydrophilic polymerdissolved in the organic solvent preferably is a polyvinylpyrrolidonehaving a molecular weight ranging from 10,000 to 5,000, a(N-methylpyrrolidone) or a N-methylpiperidone-2). These selected cycliclactams are very soluble in water and produce co-precipitates which areeasily and wholly soluble in water.

The organic solvent usually is a solvent which both dissolves the veryhydrophilic polymer and the active ingredient while having asufficiently high degree of volatility to be in a position to be afterdissolution of the mixture, evaporated off without having recourseto—very strong, physical means—such as heat or vacuum. Such solvents arefor example oxygenated solvents such as ethanol, isopropanol,tetrahydrofuran, isopropyl ether, acetone, methy ethyl ketone,tetrahydropyran, or chlorinated solvents such as methylene chloride oreven mixtures in various proportions of these same solvents.

The optionally added surface-active agent preferably is a non-ionicsurface active agent selected from the polyoxyethylenic esters ofsorbitan and saturated or unsaturated fatty acids having at least 8carbon atoms; polyoxyethylenic ethers of fatty alcohols of at least 8carbon atoms and the polyoxyethylenic esters of stearic acid.

The non-ionic tensio-active agent is selected from among those having anamphiphilic character but with a hydrophilic predominancy, having aHLB>12, such as the polyoxyethylenic esters of sorbitan and fatty acidssuch as Tweens 20 to 80, the polyoxyethylenic ethers of fatty alcoholssuch as the Brijs 56, 58, 78, 96, 97, 98, 99; G 3816 and 3820, G 3910and 3920 or Ethylan D254 to 257 or Renex or Cremophor as well as thoseof Pluronic type (block-Copolymers of ethylene oxide and propylene oxidesuch as Pluronics F 68 and F 87 or Poloxamer 188).

Among the hardly water soluble active ingredients, the incorporation ofwhich in the pharmaceutical compositions of this invention may beretained, these may be cited more particularly.

-   anti-inflammatories and analgetics    -   salsalate    -   benorylate    -   oxametacine    -   piroxicam    -   nimesulide    -   floctafenine    -   ethenzamide-   immunosuppressants    -   cyclosporine-   anti-histaminics    -   terfenadine    -   brompheniramine    -   chlorpheniramine-   antifungals and anti-trichomonas    -   metronidazole    -   ornidazole    -   dapsone    -   itraconazole-   antivirals    -   cytarabin-   antipsychotics    -   sulpiride    -   sultopride-   hormones    -   estradiol and its esters    -   estrone    -   estriol    -   progesterone and its derivatives-   cardio-vascular agents    -   dobutamine    -   diltriazem    -   nifedipine and analogs-   anti-ulcerous agents    -   pirenzepine-   anti-bacterial agents    -   erythromycin    -   flumequine    -   oxytetracycline    -   piperacillin    -   cefuroxime-   anti-arrhythmic agents    -   propafenone    -   amiodarone    -   cordarone    -   flecainide    -   gallopamil    -   verapamil    -   dipyridamole    -   diisopyramide-   anti-migrainous agents    -   flunarizine    -   derivatives of ergot-   anti-depressants    -   fluvoxamine    -   fluanisone-   anti-hormones    -   flutamide-   broncho-dilators    -   tulobuterol    -   talinolol    -   prenalterol-   anxiolytics    -   thiothixene    -   trazodone    -   doxepine-   vaso-dilators    -   ethaverine    -   pentoxyphylline    -   eburnamonine-   diuretics    -   furosenide    -   triamterene    -   torasemide-   anti-spasmodics    -   flavoxate    -   trimebutine-   agents inhibiting the excretion of calcium    -   clodronate    -   pamidronate-   anti-coagulating agents    -   pindione    -   tromexan        and/or hypocholesterolemiants, and more precisely the        derivatives of clofibric acid such as for example    -   clofibrate    -   clofibride    -   fenofibrate    -   gemfibrozil    -   benzafibrate        and finally mainly metronidazole, itraconazole, cyclosporine,        piperacilline and cefuroxime.

Principally, the content of active ingredients in the pharmaceuticalcomposition of this invention is of the same order of magnitude as withthe usual pharmaceutical composition.

A more significant attention has to be paid to the compounds which arelittle or not resorbed in the intestines such as progesterone and itsderivatives. It is preferred that the substitution in 17 α is needed inorder that the progesteronic agents are active orally (cyproteroneacetate, demegestone, promegestone, norethynodiol diacetate,medroxyprogesterone acetate . . . ) but this substitution has an effectto induce at the same time, noxious side-effects (androgenic oranti-androgenic action, estrogenic action . . . ) which are not at alldesired. It appears highly desirable to use native progesterone or aderivative of progesterone such as dihydroesterone,17α-hydroxyprogesterone for example, which does not bear anysupplemental substituent in position 17α.

The resorption of such molecules is made easier by incorporating them inthe form of a solid dispersion of the invention in an outer shell in thepresence or absence of surface-active agents. In such a medium, theprogesteronic derivative easily and quickly dissolves in the presence ofwater.

In the case of progesteronic derivatives, one may realizeco-precipitates containing from 10 to 60% by weight of activeingredient. The amount of surface active agent ranges from 0.5 to 20%related to the whole mass. The preferred content ranges from 15 to 35%for the progesteronic derivative and from 1 to 10% of surface-activerelated to the whole mass. Co-precipitates of progesteronic derivativesare obtained which dissolve practically in an integral manner in wateror in an aqueous medium in 10 to 20 minutes under stirring, depending onthe content of progesteronic derivative.

Studies performed by the applicants have shown that: A) The presence ofsurface active agents such as polysorbate 80, improves the rate ofrelease of the progesteronic derivative whatever is the co-precipitate.This improvement is all the more significant because the content ofactive ingredient increases in the sample. It is then for example thatthe average levels of dissolution of the progesteronic derivative in theco-precipitates having 30 and 50% w/w active ingredient withpolysorbate, respectively are 95 and 60% in 10 minutes as compared with55 and 18% for the same samples prepared without polysorbate. B) Therate of dissolution of the progesteronic derivative is independent ofthe content of polysorbate 80 in the co-precipitates with 20 and 30% w/wof active ingredient because the kinetics are practicallysuperimposable. On the other hand, this rate of dissolution depends onthe percentage in weight of polysorbate 80 for the co-precipitates at50% w/w.

The best kinetics are obtained with the sample containing 10% w/w ofpolysorbate 80. This result shows that a more significant amount ofsurface active agent is required to facilitate the wetting and thedissolution of a progesteronic derivative when its content is high inthe co-precipitate.

However, it has been determined that during their storage, the soliddispersions are susceptible to evolve to more thermodynamically stablestates by recrystallization or growth of dispersed particles, knowingthat time and temperature factors have a significant effect on thistransformation, and it appears necessary to study the future of theco-precipitates of progesterone/PVP and progesterone/PVP/polysorbate 80after 6 months of storage at different temperatures. The results of thestudies have shown that the kinetics of dissolution of the progesteronicderivative obtained from co-precipitates stored 6 months at 4° C., 20°C., and 37° C. do not present significative differences with freshlyprepared products whatever the temperature of preservation is andwhatever the concentration of active ingredients of the kinetics ofdissolution in the case of progesterone is.

When the organic solution brought to dryness is ground, the resultingpulverulent product can be diluted with carriers or pharmaceuticalvehicles or be subjected to a coating by fluidized bed. The achievedpharmaceutical forms can be packed in the form of tablets, sugar-coatedpills, pills, soft gelatin capsules or sachets according to the usualtechnics of the industrial galenics. It is also possible to form bycoating in a fluidized bed a granule which can be broken, screened andcompressed or kept intact, and which can be divided in tight sachetsready for administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are graphs showing the dissolution in water of 200 gramsof powder per liter.

FIGS. 3 and 4 are the percentage of dissolution of the compositions inwater.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

The performed tests have thus had as an aim to improve the kinetics ofdissolution of an active ingredient such as progesterone to improve thebioavailability of this hormone after oral administration. In a firstpart, a number of solid dispersions have been prepared by the method ofmelting/solidification and or by the method of dissolution/evaporationusing five hydrophilic excipients: saccharose distearate,polyoxyethyleneglycol 4000, polyvinyl pyrrolidone, citric acid, andphospholipids. The thus-finalized techniques have allowed to obtain, ina reproducible manner, products showing a clear improvement in thedissolution of progesterone.

Physical mixtures containing 20, 30 and 50% w/w of progesterone havebeen prepared with polyvinyl pyrrolidone (Kollidon 30 BASF) whilereplacing respectively 1, 5 or 10% w/w of PVP with the correspondingamount of polysorbate 80. The process of manufacture of these sampleswithout a tensio-active agent but the physical mixture is dissolved in asufficient amount of absolute ethanol contained in the solution,polysorbate 80. The conditions for evaporating the solvent are thosepreviously listed and the co-precipitates also show the appearance of awhite, crumbly and easily recoverable foam. The optimal diluent for theforthcoming of this study has been polyvinylpyrrolidones with which aco-precipitate containing 20% w/w of progesterone, shows a rate ofdissolution of 80% in 10 minutes.

In a second part, it has been tried to further optimize the formulationof the co-precipitates of progesterone/PVP by modifying, on one side,the concentration of the active ingredient in the samples, and/or theconditions of evaporation of the solvent, and studying on the otherside, the influence of the surface-active agent incorporated in theformulation at various concentrations. It has been stated thatpolysorbate 80 or Cremophor EL very significatively improved the rate ofdissolution of progesterone. The best results have been obtained withthe more concentrated co-precipitates.

In a third part, it has been evidenced that the kinetics of dissolutionof progesterone after 6 months storage at 4° C., 20° C. and 37° C., donot significantly change in comparison with those recorded with thefreshly prepared products when the samples contained polysorbate 80.However, as regard to the samples prepared without polysorbate 80, theincrease of the temperature may be a factor unfavorable for the goodconservation of the samples, even when the observed change results inthe improvement of the kinetics of dissolution of progesterone. It maythen be assumed that for temperatures near 37° C., some changes in thephysical properties of the co-precipitates appear, as for example, avitreous transition which thus promotes the release of the activeingredient.

From the entire results, it appears that the co-precipitates with 30 to50% w/w of polysorbate 80 in PVP show good galenical characteristics. Infact, the rates of dissolution of the hormone after storage aresuperposable to those obtained with a freshly prepared product on oneside, and provide, on the other side, a rate of dissolution higher than95% in less than 10 minutes. Another advantage of the process of thisinvention resides in the fact that the co-precipitates contain a highcontent of active ingredient and from that, it may be possible toachieve pharmaceutical formulations which are less voluminous and moreparticularly, soft gelatin capsules of small size.

I-PROGESTERONE

1. Preparation of solid dispersions according to the invention

A-Preparation of physical mixtures

Physical mixtures containing 20, 30 or 50% w/w of progesterone inpolyvinylpyrrolidone (Kollidon 30 BASF) were prepared by stirring for 10minutes with a Mixer TURBULA. For each sample, the total amount perindustrial batch was 5 g.

B-Preparation of co-precipitates of progesterone

The physical mixtures containing various proportions of progesteronewere dissolved in a sufficient amount of absolute ethanol and the soliddispersions were obtained by evaporating off the solvent under thefollowing conditions:

-   -   the speed of rotation of the flask was 100 Rd/min.    -   the temperature of the water bath was increased to 90° C.    -   the pressure in the inside of the flask was gradually increased        to 200 millibars to prevent strong boiling of alcohol and then        when the solution showed a viscous appearance, the pressure was        again decreased to 50 millibars. The remaining alcohol was        quickly removed and the co-precipitate which appeared in the        form of a very stable white foam was easily recoverable by        scratching the bottom of the flask with a spatula.

The thus-obtained samples were kept for 48 hours in an exsiccator beforebeing ground and sieved to a grain size <100 pm.

C-Preparation of co-precipitates ofprogesterone-polyvinyl-pyrrolidone-polysorbate 80

The co-precipitates were prepared by the above process and then providedthe most complete guaranties relating to stability. The followingexamples which relate to the more particular case of progesterone areonly given as a way of illustration without limiting it in any manner.

TABLE 1 preparation of co-precipitates 20% w/w with polysorbate 80Solution of polysorbate 80 Polyvinyl in ethanol Absolute Progesteronepyrrolidone (5 g/l) ethanol with 1% of 1 g 3.95 g  10 ml 80 mlpolysorbate 80 with 5% of 1 g 3.75 g  50 ml 40 ml polysorbate 80 with10% of 1 g 3.50 g 100 ml  0 polysorbate 80

TABLE 2 preparation of co-precipitates 30% w/w with polysorbate 80Solution of polysorbate 80 Polyvinyl in ethanol Absolute Progesteronepyrrolidone (5 g/l) ethanol with 1% of 1.5 g 3.45 g  10 ml 100 mlpolysorbate 80 with 5% of 1.5 g 3.25 g  50 ml 60 ml polysorbate 80 with10% of 1.5 g 3.00 g 100 ml 10 ml polysorbate 80

TABLE 3 preparation of co-precipitates at 50% w/w with polysorbate 80Solution of polysorbate 80 Polyvinyl in ethanol Absolute Progesteronepyrrolidone (5 g/l) ethanol with 1% of 2.5 g 2.45 g  10 ml 120 mlpolysorbate 80 with 5% of 2.5 g 2.25 g  50 ml 70 ml polysorbate 80 with10% of 2.5 g 2.00 g 100 ml 20 ml polysorbate 802-Study of the Kinetics of dissolutionA-Experimental method

The device for measuring utilized for the galenic control of the soliddispersions consisted of three members:-an apparatus for dissolutionDissolutest PT 6 from Erweka-a peristaltic pump 502 SR from WatsonMarlow and-a spectrophotometer coupled with an automatic apparatus fordissolution, from SAFAS.

Each test of dissolution was carried out in one liter of degassed waterat 37° C. and a pH close to neutral. A sample weighing about 5 mg ofprogesterone (i.e. 25 mg of co-melting or co-precipitate) was introducedinto each of the six reactors at time TO with a speed of stirring of thepaddles of 100 rpm. The dosing through UV absorption at 250 nm wasperformed continuously, and in closed circuit using a multi-channelperistaltic pump connecting the beakers of the Dissolutest apparatus, tothe dishes of the spectrophotometer. The latter was linked to a recorderand to a printing machine to permit the measurement at constantintervals of every 3 minutes of the variations of the optical density,themselves being proportional to the variations of concentration of theactive ingredient in the medium of dissolution.

B-Results

B.1-Kinetics of dissolution of the co-precipitate of Progesterone-PVP

The kinetics of dissolution of progesterone starting with the soliddispersions containing 20, 30 and 50% w/w of active ingredient are shownin Table 1. These results indicate that the rate of release of thehormone was dependent on the content of active ingredient in theco-precipitate. It was effectively noticed a rate of dissolution near95% in 10 minutes for the co-precipitates at 20% w/w versus 55% and 18%for the co-precipitates at 30 and 50% w/w. This result showed that thebest kinetics were obtained with the less concentrated soliddispersions, that is likely linked with a greater dispersion of theactive ingredient within the co-precipitate when its content was low inthe sample.

On the other side, it is interesting to point out that the kinetics ofdissolution of the co-precipitates with 20% w/w were more rapid thanthose recorded at the time of the preliminary studies with samples ofthe same concentration. The result may be attributed to changes in theconditions of production. While decreasing the pressure and increasingthe temperature of the water bath, the evaporation of the solvent wasmade easier and the crystallization of the active ingredient whichremains incompletely crystallized or in a more or less amorphous state,was inhibited and then the active ingredient was more soluble.

B.2-Kinetics of dissolution of the co-precipitates ofprogesterone/PVP/Polysorbate 80

The kinetics of dissolution of progesterone starting from soliddispersions containing 20, 30 and 50% w/w of active ingredient withvarious proportions without or with 1, 5 or 10% w/w of polysorbate 80are illustrated in the table IV, V, VI and VII.

TABLE IV PROGESTERONE-PVP Time co-precipitates after manufacture(minutes) 20% 30% 50% 0 0 0 0 3 77.32 33.49 5.55 6 88.65 45.79 9.76 992.93 53.38 17.06 12 95.31 57.61 18.73 15 96.74 62.85 22.30 18 97.7765.71 23.73 21 98.38 68.01 27.38 24 99.03 71.11 30.39 27 99.82 74.6833.01 30 99.90 77.79 35.07 33 99.90 80.39 37.46 36 99.90 83.17 39.12 3999.90 85.26 41.34 42 99.90 87.46 43.14 45 99.90 88.01 44.82 48 99.9089.28 46.58 51 99.90 91.26 48.80 54 99.90 92.46 50.55 57 99.90 94.2051.11 60 99.90 94.92 52.06

TABLE V PROGESTERONE-PVP 20% co-precipitates Time after manufacture withpolysorbate 80 (minutes) 1% 5% 10% 0 0 0 0 3 87.30 86.54 80.26 6 94.2094.55 92.69 9 97.15 98.90 97.40 12 99.50 99.60 100 15 99.80 100 100 18100 100 100 21 100 100 100 24 100 100 100 27 100 100 100 30 100 100 100

TABLE VI PROGESTERONE-PVP 30% precipitates Time after manufacture withpolysorbate 80 (minutes) 1% 5% 10% 0 0 0 0 3 79.59 83.44 28.66 6 88.8893.60 91.04 9 92.85 96.93 96.01 12 96.74 98.40 95 15 98.23 99.40 99.7018 99.86 99.79 100 21 100 100 100 24 100 100 100 27 100 100 100 30 100100 100

TABLE VII PROGESTERONE-PVP co-precipitates Time after manufacture withpolysorbate 80 (minutes) 20% 30% 50% 0 0 0 0 3 22.38 36.82 44.91 6 37.9351.90 60.10 9 46.42 61.50 69.70 12 54.12 67.22 74.40 15 58.65 71.9878.90 18 62.38 76.36 83.50 21 65.15 80.47 89.84 24 68.49 81.66 93.96 2770.63 83.04 95.55 30 72.38 84.52 96.79 33 74.28 86.31 98.25 36 75.3987.49 98.49 39 77.14 88.49 100 42 78.65 89.12 100 45 80.23 90.71 100 4881.57 91.76 100 51 82.38 92.58 100 54 82.93 92.93 100 57 83.88 93.17 10060 85.15 93.92 100

TABLE VIII PROGESTERONE-PVP co-precipitates Time after 6 months storageat 4° C. (minutes) 20% 30% 50% 0 0 0 0 3 78.87 32.22 8.01 6 86.80 42.7715 9 89.10 48.65 20.79 12 91 52.30 25.39 15 92.90 56.26 29.76 18 94.6058.49 33.33 21 96 60.71 37.14 24 97.80 63.17 40.24 27 98.80 65.28 42.9330 100 68.41 46.03 33 100 70.23 47.93 36 100 71.82 51.11 39 100 73.9652.14 42 100 75.07 54.20 45 100 78.88 56.35 48 100 79.93 57.62 51 10080.95 59.84 54 100 82.06 60.95 57 100 83.09 62.54 60 100 83.80 64.20

TABLE IX PROGESTERONE-PVP co-precipitates Time after 6 months storage atroom temperature (minutes) 20% 30% 50% 0 0 0 0 3 83.33 30.87 12.40 690.79 42.14 22.69 9 93.25 47.62 30.47 12 95.30 53.57 37.77 15 96.9055.95 42.85 18 97.90 60.79 47.69 21 98.80 62.30 52.22 24 99.80 64.2055.70 27 100 67.90 58.48 30 100 70.48 61.98 33 100 71.98 64.68 36 10075.16 66.81 39 100 76.90 69.67 42 100 78.57 71.58 45 100 80.32 72.93 48100 81.83 75.63 51 100 82.78 77.23 54 100 83.01 78.48 57 100 83.65 79.9960 100 85.32 81.35

TABLE X PROGESTERONE-PVP co-precipitates Time after 6 months storage at37° C. (minutes) 20% 30% 50% 0 0 0 0 3 82.69 43.73 18.02 6 90.55 65.6332.30 9 96.42 71.50 42.54 12 97.69 74.92 51.67 15 98.96 77.22 58.10 1899.44 78.09 64.21 21 100 80.01 68.33 24 100 81.77 71.91 27 100 83.0976.03 30 100 83.96 79.13 33 100 84.28 80.79 36 100 85.58 83.89 39 10086.22 85.72 42 100 87.34 86.75 45 100 88.65 88.76 48 100 89.20 90.86 51100 89.84 91.26 54 100 90.46 82.26 57 100 91.19 93.56 60 100 91.98 94.663-Study of the kinetics of dissolution after storageA-Kinetics of dissolution of the co-precipitates of Progesterone-PVP

The kinetics of dissolution of progesterone starting from soliddispersions containing 20, 30 and 50% w/w of active ingredient after sixmonths storage at 4° C., 20° C. and 37° C. are shown in tables VIII toX. As previously, it has been noticed that the rate of release of thehormone depends on its content in the co-precipitate. However, acomparison between the kinetics of dissolution after six months ofstorage, as compared to those measured with the same freshly-producedproducts, show that the increase in the temperature of storage seems toimprove the rate of dissolution of progesterone in the most concentratedco-precipitates. The most significative result has been obtained withthe co-precipitate with 50% w/w, stored at 37° C. for which a rate ofdissolution of 95% after one hour was obtained as compared to 52% forthe same product freshly produced.

B-Kinetics of dissolution of the co-precipitates ofprogesterone-PVP-polysorbate 80

The kinetics of dissolution of progesterone starting from a soliddispersion containing various proportions of polysorbate 80 and afterstorage for 6 months at 4° C., 20° C. and 37° C. are shown in the tablesX, XI and XII. These results indicate that the kinetics of release ofthe hormone starting from co-precipitates stored for 6 months at 4°, 20°and 37° C. do not present any significant difference and are practicallysuperposable to those recorded on freshly produced products. Temperaturedoes not seem to play a determinant role in the conservation of thesamples containing polysorbate 80 during the first 6 months of storage.

C-Comparative study of the phasma level of progesterone

RIA method after chromatography extraction of progesterone after oraladministration to an empty stomach in 8 healthy menopausal femalevolunteers. (Cross-over study in hospitalized volunteers which hadpreviously fasted the evening before, meal given after taking performedthe fourth hour following the ingestion of the product).

TABLE XI Ratio of the geometric Ex- averages of pression AUC the AUC vs.Studied of Cmax (ng. Utrogestan compound the results (ng/ml) Tmax (h)ml¹.b) 200 mg Co-precipitate Mean 115.46 0.69 144.71 5.66 of the SEM26.73 0.09 34.28 invention min-max 7.80- 0.50-1.00 18.62- 2 × 100 mg CV231.58 0.38 335.98 0.68 0.69 Co-precipitate Mean 67.25 0.75 73.99 3.90of the SEM 21.20 0.09 22.46 invention min-max 6.39- 0.50-1.00 15.36- 2 ×70 mg CV 167.62 0.36 209.95 0.91 0.90 Co-precipitate Mean 10.82 0.6913.39 0.56 of the SEM 5.24 0.09 3.80 invention min-max 2.52- 0.50-1.00 5.47- 2 × 35 mg CV 47.82 0.38 10.07 1.40 0.84 Utrogestan ® Mean 8.612.06 23.51 2 × 100 mg SEM 3.51 0.58 4.91 min-max 0.57- 1-6  7.13- CV27.14 0.80 51.90 1.19 0.65 ® Utrogestan is a brand name of a preparationbased on micronized ProgesteroneII-ESTRADIOL1. Preparation of solid dispersions of the inventionA-Raw materials

The used raw materials were estradiol as the hemihydrate, art.680025batch 24056446 from Schering AG (Berlin, Germany), polyvinylpyrrolidone(Kollidon 30 no. 56.0902 from BASF AG 67056 Ludwigshafen Germany). Tween80 (polyoxyethylene sorbitan mono oleate AB 397). (ICI Chemicals,Niederlassung der deutsche ICI GMBH Goldschmidtstr. 100 D 4300 Essen 1)and Absolute ethanol (no. EEC 603.002.00.5) from Distillery Hauguel76700 Gonfreville l'Orcher (F).

B-Apparatus

The apparatus to be used for the production of the solid dispersionswere an electronic weighing machine A 120 Sartorius from OSI 141 rue deJavel 75015 Paris and a rotative evaporator RE Büchi, from Roucaire 20avenue de l'Europe 78143 Velizy (F).

C-Preparation of the solid dispersions by dissolution-evaporation

The physical mixtures containing 10% estradiol w/w had the followingcomposition: 0.5 g of estradiol, 4.25 g of PVP, 0.25 g of Tween 80 i.e.50 ml of a 5 g/l solution in absolute ethanol and 20 ml of absoluteethanol enough for dissolving both estradiol and PVP. These mixtureswere dissolved each in a sufficient amount of absolute ethanol. About 50ml ethanol were needed for each gram of estradiol, 10 mol of ethanol pergram of PVP. The solid dispersions were obtained by evaporating thesolvent under reduced pressure (p=200 millibars) for 15 minutes, andthen the pressure was reduced to its minimum (about 40 millibars) for 15minutes. The temperature of the water bath was 60° C. and the speed ofrotation of the flask was 100 rounds/minute. The recovered samples wereplaced in an exsiccator for 47 hours and then were ground and screened.The galenical tests were performed on samples having granulometry lowerthan 100 micrometers.

2-Study of the kinetics of dissolution

A-Experimental method

The system of measurements used for the galenical control of the soliddispersions was made of two members: an apparatus of dissolutionDISSOLUTEST DT 6 from ERWEKA |Euraf 55 rue Deschanel 92400 Courbevoie(France)| and a peristaltic pump 505 SR WATSON-MARLOW from Prolabo. Eachtest of dissolution was performed in one liter of degassed distilledwater at 37° C. and at a pH near neutral. A sample of 4 mg of estradiol(i.e. 25 mg co-precipitate) was introduced in each of the six reactorsat time t=0 and the speed of stirring of the paddles was 100 rounds/min.The dosages by UV (absorption at 278 nm), were performed continuouslyand in a closed circuit of a multi-channel peristaltic pump, connectingthe beakers of the Dissolutest to the dishes of the spectrophometer. Thelatter was linked to a recorder and to a printing machine to permit themeasurement at steady intervals of every 3 minutes of the variations ofthe optical density, themselves being proportional to the variations ofthe concentration of the active ingredient in the dissolution medium.

B-Results

The kinetics of dissolution of estradiol from the solid dispersions at10% w/w are presented in FIG. 1. From this table, it may be seen thatfor the co-precipitates with 10% w/w of estradiol, an instantaneousdissolution which allows one to reach a percentage of dissolved compoundof at least 65% in 3 minutes and at least 75% in 15 minutes.

TABLE XII Estradiol 10%-PVP 75% Time Polysorbate 80 - 5% w/wco-precipitates (minutes) Dish 1 Dish 2 Dish 3 Dish 4 Dish 5 Dish 6 0 00 0 0 0 0 3 67.36 67.36 67.36 63.15 67.36 67.36 6 71.57 71.51 71.5163.15 71.57 71.57 9 71.51 71.51 71.51 63.15 71.57 71.57 12 71.57 75.7875.78 67.36 75.78 75.78 15 75.78 75.78 75.78 67.36 75.78 75.78 18 71.5775.78 75.78 67.36 75.78 75.78 21 75.78 75.78 75.78 67.36 75.78 75.78 2475.78 75.78 75.78 67.36 75.78 75.78 27 75.78 75.78 75.78 67.36 75.7875.78 30 80 75.78 80 67.36 80 80 33 84.21 75.78 80 67.36 80 80 33 84.2175.78 80 67.36 80 80III-MIXTURES OF PROGESTERONE-ESTRADIOL

1-Production of solid dispersions of the invention

A-Raw materials

The used raw materials were the same as those used in the case ofestradiol (chapter IV) to which progesterone was added (USP and EP batch347 JA) from Upjohn Company Fine Chemical Division, Kalamazoo, Mich.40991 (USA).

B-Apparatus

The apparatus was also the same than that used in the case of estradiol.

C-Production of solid dispersions by dissolution/evaporation

The performed co-precipitates had the following composition: 2.5 g ofprogesterone, 0.05 g of estradiol, 2.2 g of PVP and 0.25 g i.e. 50 ml ofa solution at 5 g/l of Tween 80 in absolute ethanol. 103 ml of absoluteethanol were needed for the complete dissolution of the variouscomponents (50 ml absolute ethanol for 1 g of progesterone, 10 ml for 1g of estradiol). The solid dispersions were obtained by evaporation ofthe solvent under vacuum (P=200 millibars) for 25 minutes, and then thepressure was decreased to its minimum (about 40 millibars) for 35minutes. The temperature of the water bath was 60° C. and the speed ofrotation of the flask was 100 rounds/minute. The thus-recovered sampleswere placed in an exsiccator for 48 hours and then were ground andsieved. The galenical tests were performed on samples having agranulometry lower than 100 micrometers. The co-precipitates obtainedbefore staying in the exsiccator were in the form of a crystallineblock, pale yellow or white, and small crystalline clusters were alsorecovered.

2-Study of the kinetics of dissolution

These tests of dissolution were performed in water and the usedco-precipitates contained 50% progesterone and 1% estradiol. Two testswere performed: one with 200 mg of powder per liter of water and theother with 20 mg of powder per liter of water. The performance of thesetwo tests may be explained by the fact that estradiol cannot be detectedin a sample containing 20 mg of powder per liter of water and it hadbeen necessary to use a sample of 200 mg of powder per liter of water tobe able to detect estradiol.

Results: Test 1 (200 mg powder for 1 liter water)

TABLE XIII Content in estradiol Content in progesterone PercentagePercentage Percentage Percentage in in in in relation to relation torelation to relation to the the the Time theoretical measuredtheoretical measured (min.) mg/l content content mg/l content content 3<0.3 <15 <25 0.78 0.8 1.0 6 <0.3 <15 <25 4.56 4.6 6.0 9 0.46 23 38.36.33 6.3 8.3 12 0.76 38 63.3 6.58 6.6 8.6 15 0.82 41 68.3 6.30 6.3 8.218 0.86 43 71.7 6.43 6.4 8.4 Test 2 (20 mg powder per liter of water)

TABLE XIV Content in estradiol Content in progesterone PercentagePercentage Percentage Percentage in in in in relation to relation torelation to relation to the the the de- Time theoretical determinedtheoretical termined (min.) mg/l value content mg/l value content 3 ND0.27 2.7 3.5 6 ND 2.99 29.9 39.0 9 ND 3.87 38.7 50.5 12 ND 4.28 42.855.9 15 ND 4.49 44.9 58.6 18 ND 4.54 45.4 59.3 ND: Not detectable3-Profiles of dissolution of the solid mixture progesterone-estradiol inwater

The curves of dissolution versus time are presented below: FIG. 1: (testof dissolution in water of 200 mg of powder per liter), FIG. 2: (test ofdissolution in water of 20 mg of powder per liter), FIG. 3: (test ofdissolution in water of 200 mg of powder per liter) and FIG. 4:determination of the percentage of progesterone dissolved in waterstarting of 20 mg of powder per liter of water.

IV-SOLID DISPERSIONS WITH FENOFIBRATE

1-Production of the solid dispersions of the invention

A-Raw materials

Fenofibrate (batch F 0092×100) from Schweizerhalt France-Deshors 17 Bdde Montmorency 75016 Paris, polyvinylpyrrolidone (Kollidon 30 - Nr 56 -0902) from BASF AG 67056 Ludwigshafen Germany, Tween 80 (polyoxyethylenesorbitan monooleate) batch AB 397 (ICI Chemicals, Niederlassung derdeutsche ICI GMBH, Goldschmidstr 100 D-4300 Essen 1) and absoluteethanol from Distillery Hauguel 76700 Gonfreville l'Orcher (F).

B-Apparatus

The needed material was exactly the same as that which had been used toproduce the foregoing co-precipitates.

C-production of the solid dispersions by dissolution-evaporation

Five series of co-precipitates were achieved, each including 6 differentsamples.

TABLE XV Series 1 2 3 4 5 Fenofibrate 2.5 gr 2 gr 1.5 gr 1 gr 0.5 gr PVPK30 2.25 gr 2.75 gr 3.25 gr 3.75 gr 4.25 gr Tween 80 0.25 gr 0.25 gr0.25 gr 0.25 gr 0.25 gr Absolute 103 ml 81 ml 61 ml 41 ml 21 ml ethanol

The solid dispersions were produced by evaporating under vacuum (P=205millibars) for 25 minutes and then the pressure was decreased to itsminimum (40 millibars) for 25 minutes. The temperature of the water bathwas 60° C. and the speed of rotation of the flask was 100 rounds perminute. The duration of the evaporation was adapted, depending on theamount of absolute ethanol added for dissolving the products and then asa function of the series of the co-precipitates. The Samples with 2.5 gof fenofibrate had a yellowish appearance and formed a pellet more orless viscous, after one hour of evaporation at the minimal pressure.

The more the pressure was decreased (the amount of absolute ethanoladded, decreasing from this fact), the more the recovered samples wereclumsy, in the form of fine powder or granules. The color was white andbright and the co-precipitates appeared as being very dry. Thethus-recovered samples were placed in an exsiccator for 48 hours andthen were ground and sieved. The galenical tests were performed onsamples of grain size lower than 100 micrometers.

2-Study of the kinetics of dissolution

A-Experimental method

This was identical to that used for the study of the kinetics ofdissolution for the co-precipitates of estradiol.

B-Results

The maximal solubility of fenofibrate in water had been previouslydetermined which was less than 3 mg/l. The co-precipitates producedabove respectively contained 50%, 40%, 30%, 20% and 10% by weight offenofibrate. When someone wanted to introduce in the reactors an amountof fenofibrate which allowed the total solubilization in 1 liter ofwater, he would need to weigh respectively 6 mg, 7.5 mg, 10 mg, 15 mgand 30 mg of co-precipitates. This accuracy in this measurement whichwas due to minute but unavoidable losses due to handling, cannot beachieved.

Therefore, it had been decided to prepare a calibrating range at 5 mg/las for progesterone and to determine the kinetics of dissolution whileintroducing an equivalent amount of co-precipitate. This study permittedto quantify the amount of solubilized fenofibrate and in the course ofthis test, a recrystallization of fenofibrate had been observed. Theresults are shown in tables XVI and XVII respectively, the calibratingrange and the kinetics of dissolution of fenofibrate in theco-precipitates at 10% w/w (randomly selected series which wasrepresentative of a phenomenon common to the other co-precipitates).

TABLE XVI Time Calibrating range of Fenofibrate at 5 mg/l (minutes) Dish1 Dish 2 Dish 3 Dish 4 Dish 5 Dish 6 0 0 0 0 0 0 0 3 95.26 95.26 98.9493.68 94.21 93.15 6 92.1 92.1 95.78 91.05 92.1 90.52 9 87.89 87.89 91.0586.31 87.89 85.78 12 83.68 83.68 86.31 82.1 83.15 80.52 15 80.52 80.5283.15 78.42 80 76.84 18 77.89 77.36 80 75.26 77.36 74.21 21 74.73 74.7376.84 71.57 73.68 71.05 24 72.1 72.1 73.68 68.94 71.05 68.42 27 70 7071.57 66.84 68.94 66.31 30 68.42 67.89 69.47 64.73 67.36 64.73

The decrease of these kinetics of dissolution was exclusively due to thesensitivity of this formulation to the light and to the fact that thedosage was performed by UV Spectro-photometry at 278 nm, that resultedin a degradation of the formulation. This degradation was absolutely notdue to the method of preparation of the co-precipitates but only to thetechnique of reading.

TABLE XVII Co-precipitates fenotibeate 10% - PVP 25% Time Polysorbate80 - 5% w/w (minutes) Dish 1 Dish 2 Dish 3 Dish 4 Dish 5 Dish 6 0 0 0 00 0 0 3 60.52 34.21 59.47 57.36 55.26 61.95 6 45.26 13.15 51.57 42.6323.15 31.95 9 36.31 10.52 34.20 36.84 14.52 13.15 12 31.15 9.42 31.5734.23 9.42 11.52 15 30 8.94 28.94 32.1 9.42 11.52 18 28.94 8.94 30.5230.05 8.94 10 21 27.89 8.42 27.36 29.43 8.94 10 24 28.94 8.42 27.3629.42 8.942 10 27 26.84 8.42 25.26 30.52 8.94 10 30 25.78 8.42 26.3127.89 8.94 9.42 33 25.26 8.42 26.31 26.84 8.42 9.47 36 25.26 8.42 24.7327.89 8.42 9.47 39 25.26 8.42 23.68 29.47 8.42 9.47 42 25.26 8.42 23.6827.36 8.42 9.47 45 25.26 8.42 23.68 27.36 8.42 9.47 48 24.73 8.42 23.6827.36 8.42 9.47 51 24.73 8.42 24.73 26.84 8.42 9.47 54 26.31 8.42 22.6326.84 8.42 9.47 57 23.68 8.94 23.15 26.84 8.42 9.47 60 23.68 8.94 23.1527.36 8.42 9.47

Herein also the UV Spectro-photometry was wholly responsible for thedecrease of the kinetics of dissolution.

V-SOLID DISPERSIONS WITH MEDROXY PROGESTERONE ACETATE

1-Production of the solid dispersions of the invention

Five series of co-precipitates were realized each including six samples.

The amount of Medroxy progesterone acetate in each series was 0.5 g andthat of polyvinylpyrrolidone ranged from 2 to 5 g. The solid dispersionswere prepared according to the method described in example IV.

The solubility of Medroxy progesterone acetate in water is very low. Thedosage of the amount of Medroxy progesterone acetate thus dissolved inwater was determined by spectrophotometry at 241 nm.

The percentage of dissolved compound was about complete in 30 minutes atroom temperature.

Various modification of the process and products of the invention may bemade without departing from the spirit or scope thereof and it is to beunderstood that the invention is intended to be limited only as definedby the appended claims.

1. A process for the production of a solid dispersion of 1 to 20% byweight of a surface active agent, 10 to 60% by weight of at least onetherapeutic agent selected from the group consisting of progesterone anda mixture of progesterone and estradiol or an ester or ether thereof ina hydrophilic carrier having enhanced solubility in an aqueous mediacomprising dissolving the therapeutic agent in a volatile organicsolvent containing a very hydrophilic polymer and the surface activeagent in the said percentage and without strong heat or vacuumevaporating the solvent to dryness to form a co-precipitate oftherapeutic agent and , hydrophilic polymer and surface active agent. 2.The process of claim 1 wherein the co-precipitate is ground and screenedto obtain a uniform powder.
 3. The process of claim 1 wherein theevaporation to dryness of the organic solution is carried out in afluidized bed of air.
 4. The process of claim 1 wherein the volatileorganic solvent is an oxygenated solvent or a chlorinated solvent. 5.The process of claim 1 wherein the volatile organic solvent is analkanol.
 6. The process of claim 1 wherein the volatile organic solventis methylene chloride.
 7. The process of claim 1 wherein the volatileorganic solvent is selected from the group consisting of ethanol,isopropanol and terbutanol.
 8. The process of claim 1 wherein the veryhydrophilic polymer is selected from the group consisting ofpolyvinylpyrrolidones, N-methylpyrrolidones, N-methylcaprolactam and theN-methylpiperidin 2-ones.
 9. The process of claim 1 wherein the polymeris polyvinyl pyrrolidones having a molecular weight ranging from 10.0010,000 to 50,000.
 10. The process of claim 1 wherein the surface-activeagent is a non-ionic surface-active agent.
 11. The process of claim 1wherein the non-ionic surface active agent is selected from the groupconsisting of polyoxyethylenic ester of sorbitan and saturated andunsaturated fatty acids having at least 8 carbon atoms, polyoxyethylenicethers of fatty alcohols having at least 8 carbon atoms,polyoxyethylenic ethers of fatty alcohols having at least 8 carbon atomsand polyoxyethylenic esters of stearic acids.
 12. The process of claim 1wherein the surface-active agent is a polysorbate.
 13. A soliddispersion with enhanced bioavailability of 1 to 20% by weight of asurface active agent, 10 to 60% by weight of at least one therapeuticagent selected from the group consisting of progesterone and an agentselected from the group consisting of progesterone and a mixture ofprogesterone and estradiol or an ester or ether thereof in a hydrophiliccarrier having enhanced solubility in an aqueous media comprisingdissolving the therapeutic agent in a volatile organic solventcontaining a very hydrophilic polymer and the surface active agent inthe said percentage and without strong heat or vacuum evaporating thesolvent to dryness to form a co-precipitate of therapeutic agent and ,hydrophilic polymer and surface active agent.
 14. A solid dispersionwith enhanced bioavilability of claim 13 wherein the therapeutic agentis a mixture of estradiol or one of its ester or ethers, andprogesterone.
 15. A pharmaceutical composition containing the soliddispersions obtained by claim 2 wherein the solid dispersion oftherapeutic agents are admixed with an inert non-toxicpharmaceutically-acceptable carrier.
 16. A pharmaceutical composition ofclaim 15 wherein the inert carrier is constituted by neutral pellets ofstarch.
 17. A pharmaceutical composition of claim 15 wherein the inertcarrier is an aqueous sterile medium.
 18. A method for treatingdisorders connected with a hormonal insufficiency comprisingadministering to a female patient in need of such a therapy, a safe buteffective amount of a therapeutic agent consisting of progesterone orprogesterone and estradiol or an ether or ester thereof in the form of asolid dispersion obtained by the process of claim
 1. 19. The method ofclaim 18 wherein the hormonal insufficiency is a luteal anestro-progestative insufficiency and the therapeutic agent is a mixtureof estradiol and progesterone.
 20. The method of claim 18 wherein thehormonal insufficiency is an estro-progestative insufficiency and thetherapeutic agent is a mixture of estradiol and progesterone.